Depression is common in those on dialysis and is an independent risk factor for hospitalization and death. Recent studies from my laboratory have shown that about 20% of patients with chronic kidney disease (CKD) not on dialysis suffer from a major depressive episode (MDE) and are twice as likely to be hospitalized, initiate dialysis or die within a year as compared to those without a MDE. However, only a minority of CKD patients with depression are treated with antidepressants. A major reason for low treatment rates in those with CKD is lack of studies that support the efficacy and safety of antidepressants in CKD patients. The Sertraline AntiDepressant Heart Attack Randomized Trial showed benefit of serotonin-selective reuptake inhibitor (SSRI) sertraline on cardiovascular outcomes but excluded patients with moderate to severe CKD. Given the excessive rates of cardiovascular (CV) death in CKD patients, it becomes imperative to investigate whether treatment of depression is safe and efficacious in these patients. This information is needed to design an outcomes trial to determine if treatment of depression saves lives and improves quality of life in this population. In this application, I propose a pilot study to test the hypothesis that short-term treatment of a MDE with sertraline will result in improvement in depression symptom severity and quality of life in patients with predialysis stages 3b-5 CKD. I further hypothesize that treatment of MDE with sertraline is safe and well- tolerated in these patients. The aims of this study are to 1) determine if treatment with sertraline, as compared with placebo, results in an improvement in depression symptom severity and overall function and quality of life. I will use a randomized, double-blinded, placebo-controlled flexible-dose 12-week trial involving 200 subjects with predialysis stages 3-5 CKD; and assess the Work and Social Adjustment Scale and Kidney Disease Quality of Life Survey (KDQOL-SF), respectively; 2) determine if sertraline, as compared with placebo, is tolerable and safe. This will be assessed by a) proportion in each group with serious adverse events including bleeding requiring blood transfusion or hospitalization; b) type and severity of side effects reported on the Systemic Assessment for Treatment Emergent Effects scale; c) proportion in each group with side effects reported on the Frequency, Intensity and Burden of Side Effects Rating scale; d) reduction in platelet aggregation and activation from baseline in the sertraline as compared with placebo group, and whether this reduction correlates with higher plasma sertraline levels; 3) In exploratory analyses, I will also investigate mechanisms by which sertraline may affect outcomes by evaluating change in: a) nutritional status; b) adherence to prescribed medications; c) cognitive functioning; and d) markers of inflammation; I will also collect data on death, hospitalizations, and dialysis initiation at 6 and 12 months after randomization. The latter information will be used for power calculations to determine the feasibility of conducting a large-scale trial to investigate whether treatment of depression improves outcomes in CKD.